Abstract Pneumonia is the most prevalent cause of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) with as high as 40% mortality. Trauma-induced immune dysfunction enhances susceptibility to secondary infections that are a significant cause of mortality in hospital ICUs, and the bacterial pathogen Pseudomonas aeruginosa is a common source of nosocomial pneumonia. Neutrophils, the most abundant leukocyte in the circulation, are critical for host defense against bacterial pathogens, but they also induce bystander tissue injury due to the non-specific and cytotoxic nature of their antimicrobial arsenal. The effects of trauma on neutrophils contribute to immune dysfunction and include a significant deficit in neutrophil recruitment coupled with a primed phenotype associated with inducing tissue damage. Antibiotic-resistant bacterial infections are increasing in prevalence, underscoring the clinical need for complementary therapies that enhance the innate immune response, but do so in a manner that does not exacerbate ALI. During the innate immune response to bacterial pneumonia, neutrophils must exit the circulation and migrate into the lung airspaces. However, excessive recruitment and/or activation of neutrophils can result in tissue damage, lung injury and respiratory failure. Integrins are adhesion receptors that play key roles in neutrophil homing throughout the body. Integrin ligand binding affinity and adhesive function is regulated structurally by the intracellular proteins Talin-1 and Kindlin-3, which bind to the integrin cytoplasmic tail. Although integrin activation is essential for neutrophil recruitment from the systemic circulation, we have now shown, counterintuitively, that neutrophils with defective or antagonized ?2 integrin activation exhibit enhanced entry into the lung interstitium and airspaces in response to P. aeruginosa. Here, we will implement a mouse model of P. aeruginosa pneumonia that is secondary to hemorrhagic shock, to replicate its clinical manifestation in individuals with compromised immune function. We hypothesize that neutrophil recruitment during bacterial pneumonia is enhanced, but ALI is attenuated, when ?2 integrin activation is defective or inhibited. In Aim 1, we will evaluate the effect of Talin-1/Kindlin-3 deficiency on neutrophil trafficking, ALI and host defense during secondary pseudomonal pneumonia. In Aim 2, we will characterize and evaluate neutrophil recruitment, host defense and ALI to a range of clinical P. aeruginosa isolates, and determine the efficacy of several drug compounds that modulate ?2 integrin activity. In Aim 3, a collaboration with Project 1, we will use a mouse model of pneumonia caused by methicillin-resistant Staphylococcus aureus to evaluate several drug compounds targeting the thioredoxin system. Upon completing this work, we will have a greater mechanistic understanding of neutrophil trafficking and activation in the lungs, and how this relates to ALI and bacterial clearance. Our studies are an essential step in identifying therapeutic targets to modify the immune response to supplement antibiotic therapies, while maintaining the balance between host defense and tissue damage.